使用一种强效的[225Ac]锕标记抗HER2抗体-药物放射性缀合物实现HER2阳性曲妥珠单抗耐药异种移植瘤的完全缓解。
Complete Remissions of HER2-Positive Trastuzumab-Resistant Xenografts Using a Potent [225Ac]Ac-Labeled Anti-HER2 Antibody-Drug Radioconjugate.
作者信息
Pougoue Ketchemen Jessica, Njotu Fabrice Ngoh, Babeker Hanan, Monzer Alissar, Nwangele Emmanuel, Tikum Anjong Florence, Henning Nikita, Hassani Nava, Frye Sarah, Perron Randy, Byrne Chris, Didychuk Candice, Qi Qi, Bannister Laura, Doroudi Alireza, Fonge Humphrey
机构信息
Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
Axe Oncologie, Centre de Recherche du CHU de Québec-Université Laval, Québec, Canada.
出版信息
Clin Cancer Res. 2025 Feb 17;31(4):685-696. doi: 10.1158/1078-0432.CCR-24-1779.
PURPOSE
There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted α therapies. Antibody-drug conjugates (ADC) are highly cytotoxic. Combining [225Ac]Ac with an ADC to develop an antibody-drug radioconjugate [225Ac]Ac-macropa-trastuzumab(T)-PEG6-emtansine (DM1), is expected to be more effective than its ADC (T-PEG6-DM1) against breast cancer.
EXPERIMENTAL DESIGN
[89Zr]Zr-p-isothiocyanatobenzyl desferrioxamine (DFO)-T-PEG6-DM1 (imaging) and [225Ac]Ac-macropa-T-PEG6-DM1 (radiotherapy) were developed. Biodistribution and safety evaluations of [225Ac]Ac-macropa-T-PEG6-DM1 were carried out in non-tumor-bearing BALB/c mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO-T-PEG6-DM1, and radiotherapy using [225Ac]Ac-macropa-T-PEG6-DM1 was carried out in athymic BALB/c nude mice bearing trastuzumab-resistant HCC1954 and trastuzumab-DM1 (T-DM1)/trastuzumab-resistant JIMT-1 tumor-bearing mice.
RESULTS
After 7 days of incubation at 37°C, [225Ac]Ac-macropa-T-PEG6-DM1 was stable in both human serum (89.2% ± 0.9%) and PBS (82.8% ± 0.4%). T-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-macropa-T-PEG6-DM1 (3 × 18 kBq) administered separately in non-tumor-bearing mice 10 days apart were well tolerated biochemically and hematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO-T-PEG6-DM1 in tumor-bearing mice at 120 hours after injection: 38.1% ± 2.8% IA/g (HCC1954) and 14.6% ± 1% IA/g (JIMT-1). In HCC1954 tumor-bearing mice, all treatment groups had complete remission (8/8), indicative of the responsiveness of the xenograft to T-DM1-based treatments, whereas for JIMT-1 xenografts (having 1/8 complete remission) at 23 days after treatment, tumor volumes were 332.1 ± 77.5 vs. 244.6 ± 63 vs. 417.9 ± 62.1 vs. 102.4 ± 18.5 for the saline (negative control), T-DM1 (positive control), T-PEG6-DM1, and [225Ac]Ac-macropa-T-PEG6-DM1, respectively.
CONCLUSIONS
[225Ac]Ac-macropa-T-PEG6-DM1 is more potent than ADC against trastuzumab-resistant breast cancer and necessitates clinical translation.
目的
人们对使用锕 - 225（[225Ac]Ac）开发靶向α疗法有着浓厚的兴趣。抗体药物偶联物（ADC）具有高度细胞毒性。将[225Ac]Ac与ADC结合以开发抗体药物放射性偶联物[225Ac]Ac - 大分子曲妥珠单抗（T）-聚乙二醇6 - 依坦西普（DM1），预计在治疗乳腺癌方面比其ADC（T - 聚乙二醇6 - DM1）更有效。
实验设计
制备了[89Zr]Zr - 对异硫氰酸苄基去铁胺（DFO）-T - 聚乙二醇6 - DM1（用于成像）和[225Ac]Ac - 大分子-T - 聚乙二醇6 - DM1（用于放射治疗）。在无肿瘤的BALB/c小鼠中对[225Ac]Ac - 大分子-T - 聚乙二醇6 - DM1进行生物分布和安全性评估。使用[89Zr]Zr - DFO - T - 聚乙二醇6 - DM1进行小动物正电子发射断层显像（MicroPET）成像和生物分布研究，并在携带曲妥珠单抗耐药的HCC1954肿瘤的无胸腺BALB/c裸鼠以及携带曲妥珠单抗 - DM1（T - DM1）/曲妥珠单抗耐药的JIMT - 1肿瘤的小鼠中使用[225Ac]Ac - 大分子-T - 聚乙二醇6 - DM1进行放射治疗。
结果
在37°C孵育7天后，[225Ac]Ac - 大分子-T - 聚乙二醇6 - DM1在人血清（89.2% ± 0.9%）和磷酸盐缓冲液（PBS）（82.8% ± 0.4%）中均稳定。在无肿瘤小鼠中，分别间隔10天给予T - 聚乙二醇6 - DM1（8 mg/kg）和[225Ac]Ac - 大分子-T - 聚乙二醇6 - DM1（3×18 kBq），生化和血液学方面耐受性良好。成像和生物分布显示，注射后120小时，携带肿瘤的小鼠中[89Zr]Zr - DFO - T - 聚乙二醇6 - DM1在肿瘤中的摄取量很高：HCC1954肿瘤为38.1% ± 2.8%注射剂量每克组织（IA/g），JIMT - 1肿瘤为14.6% ± 1% IA/g。在携带HCC1954肿瘤的小鼠中，所有治疗组均完全缓解（8/8），表明异种移植瘤对基于T - DM1的治疗有反应，而对于JIMT - 1异种移植瘤（治疗后23天有1/8完全缓解），生理盐水（阴性对照）、T - DM1（阳性对照）、T - 聚乙二醇6 - DM1和[225Ac]Ac - 大分子-T - 聚乙二醇6 - DM1组的肿瘤体积分别为332.1 ± 77.5、244.6 ± 63、417.9 ± 62.1和102.4 ± 18.5。
结论
[225Ac]Ac - 大分子-T - 聚乙二醇6 - DM1在治疗曲妥珠单抗耐药的乳腺癌方面比ADC更有效，有必要进行临床转化。
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